Unleashing the power of NK cells in anticancer immunotherapy

Abstract

Due to their physiological role in removing damaged cells, natural killer (NK) cells represent ideal candidates for cellular immunotherapy in the treatment of cancer. Thereby, the cytotoxicity of NK cells is regulated by signals on both, the NK cells as well as the targeted tumor cells, and the interplay and balance of these signals determine the killing capacity of NK cells. One promising avenue in cancer treatment is therefore the combination of NK cell therapy with agents that either help to increase the killing capacity of NK cells or sensitize tumor cells to an NK cell-mediated attack. In this mini-review, we present different strategies that can be explored to unleash the potential of NK cell immunotherapy. In particular, we summarize how modulation of apoptosis signaling within tumor cells can be exploited to sensitize tumor cells to NK cell-mediated cytotoxicity.

Keywords: Apoptosis; Cancer; Immunotherapy; Natural killer cells.

Fig. 1

Proapoptotic therapeutics may potentiate NK cell-mediated cytotoxicity. Apoptosis can be initiated either at the mitochondria (intrinsic apoptosis) or upon ligation of death receptors on the plasma membrane (extrinsic apoptosis). This results in apoptosis signaling illustrated using black arrows. Apoptosis can be modulated using (a) Smac mimetics, (b) BH3 mimetics, (c) activators of p53, or (d) TRAIL agonists, thus overcoming apoptosis blockades within the tumor cell and facilitating NK cell-mediated attack, illustrated using gray arrows

Fig. 2

Modulation of the immune system using either IMiDs or ICB

Fig. 3

Effects of HMAs, TRAIL agonists, as well as kinase inhibitors